Project summary ? Immunomodulatory therapies for complex musculoskeletal trauma There are no standard therapies or surgical procedures in the clinic currently approved or used for the treatment of bone fracture with concurrent muscle trauma. The current tissue engineering and regenerative medicine paradigm also primarily focuses on treatments for isolated tissue injures (i.e. bone, skeletal muscle, etc.). Our previous work in a rat composite muscle-bone injury model has shown that VML injury to the tibialis anterior (TA) muscle results in prolonged and heightened inflammation that delays tibia fracture healing. Systemic as well as local administration of FK-506, an immunomodulatory drug, was able to mitigate inflammation in the VML injured muscle and rescue fracture healing. The overall objective of this proposal is to develop and evaluate an immunomodulatory biomaterial therapy for concomitant muscle-bone trauma. In the proposed work, biomimetic sponges will be loaded with FK-506 and implanted in a tibia fracture model with concomitant VML injury. We hypothesize that a combination of immune-modulatory and regenerative therapies will restore the biochemical communication between muscle and bone to maximize recovery of the traumatized limb. Specific Aim 1: To determine the effect of FK-506 loaded biomimetic sponges on immune and mesenchymal stem cell function in vitro. Specific Aim 2: To determine the effect of FK-506 loaded biomimetic sponges on muscle regeneration and fracture repair in a rat model of composite trauma.